| Patients with high-risk localized prostate cancer have a high recurrence rate following primary therapy. Neoadjuvant chemotherapy has been shown to be beneficial in reducing recurrence rates in some tumor types, but has yet to be of proven benefit in prostate cancer. I utilized tissue resources from a phase II clinical trial of neoadjuvant chemotherapy with docetaxel and mitoxantrone in patients with high-risk localized prostate cancer to identify molecular alterations after chemotherapy, and correlated these alterations with clinical indicators of tumor response.;A chemotherapy-induced profile was generated by a direct comparison of expression changes between pre-treatment and post-treatment cancerous epithelia from prostate. After excluding genes previously shown to be influenced by the radical prostatectomy procedure, we identified 51 genes with significant transcript level alterations following chemotherapy. This group included several cytokines including GDF15, IL8, CXCL10, IL1B, and CCL2. In vitro analyses confirmed overexpression of GDF15 may confer resistance to chemotherapy in prostate cancer cells.;Gene expression changes after chemotherapy were further correlated with clinical outcomes including percentage of PSA decline and PSA-relapse free survival. Several chemokines and chemokine pathways were found to be associated with the percentage of PSA decline. Expression changes of IL8 and CXCL10 measured by qRT-PCR were significantly and negatively associated with the percentage of PSA decline. Further, in vitro tests showed only IL1B influenced chemosensitivity of prostate cancer cells.;When correlating expression profiles with PSA-relapse free survival, I found patients with a positive post-chemotherapy change in the expression of monoamine oxidase A (MAOA) have a 1.55 fold higher risk to have a PSA relapse compared with patients with negative post-chemotherapy MAOA expression change, as determined by a multivariate Cox Proportional Hazards Model. In vitro studies confirmed the influence of MAOA on chemoresistance and determined that MAOA inhibitors produce additive effects on docetaxel-mediated prostate cancer cell growth inhibition.;In summary, genes and pathways that may contribute to chemotherapy resistance and response were identified. Development of small molecules or monoclonal antibodies capable of modifying cytokine activity, and utilizing existing drugs such as MAOA inhibitors may augment the effectiveness of chemotherapy response in patients with prostate cancer. |
